PET IMAGING STUDY OF BRAIN VMAT2 IN HUMAN METHAMPHETAMINE USERS

人类冰毒使用者大脑 VMAT2 的 PET 成像研究

• 批准号: 8044827
• 负责人: STEPHEN John KISH
• 金额: $ 21.91万
• 依托单位: CENTRE FOR ADDICTION AND MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044827
• 关键词: Abstinence; Animals; Autopsy; Behavior; Behavioral; Binding; Biological Markers; Brain; Brain imaging; Chronic; Cognitive; Control Groups; Corpus striatum structure; Data; Development; Dopamine; Drug usage; Drug user; Functional disorder; Goals; Human; Image; Imaging Device; Intervention; Longitudinal Studies; Measures; Methamphetamine; Neurology; Neuroprotective Agents; Neurotransmitters; Parkinson Disease; Patients; Performance; Pharmaceutical Preparations; Positron-Emission Tomography; Research Design; Research Personnel; Selection for Treatments; Synaptic Vesicles; Testing; Work; addiction; base; design; dihydrotetrabenazine; drug abstinence; in vivo; indexing; monoamine; psychostimulant; public health relevance; tool; vesicular monoamine transporter

DESCRIPTION (provided by applicant): PET IMAGING STUDY OF BRAIN VMAT2 IN HUMAN METHAMPHETAMINE USERS OBJECTIVE. Our broad goal is to obtain brain imaging data in human methamphetamine (MA) users that could help in development of the vesicular monoamine transporter (VMAT2) as a biomarker to explain pathophysiology and guide clinicians to more appropriate treatment interventions in the drug users. VMAT2 is the synaptic vesicle transporter responsible for monoamine neurotransmitter packaging in human brain, is predominantly localized to dopaminergic terminals in human striatum, and is now proposed in this application as a new tool to investigate vesicular dopamine status in psychostimulant users. BACKGROUND. At present there exists no useful treatment for addiction to the stimulant MA. Although controversial, we believe that a brain deficiency of the neurotransmitter dopamine, as suggested by our postmortem brain findings, might be responsible for some of the behavioural (especially cognitive) problems of MA users. However, in vivo data suggesting dopamine deficiency in MA users are lacking. In a pilot positron emission tomography (PET) study of MA users we discovered, unexpectedly, that striatal (+)- [11C]DTBZ binding to VMAT2 was increased during early abstinence, a finding which can be explained by decreased competition between dopamine (reduced in some MA users) and (+)-[11C]DTBZ binding to VMAT2. As an in vivo biomarker of vesicular dopamine status might be helpful in selecting the most appropriate treatment for MA users, there is need to confirm these findings in a representative number of subjects and establish in a longitudinal study whether binding levels do or do not decline in early abstinence. SPECIFIC AIM, DESIGN, AND HYPOTHESIS. Our major SPECIFIC AIM is to measure by PET imaging striatal (+)-[11C]DTBZ binding in a representative number of chronic MA users, with each user assessed at 4-7, 12-15, and 28-30 days following last use of the drug, and in a matched control group. Based on our pilot data, our major working HYPOTHESIS is that striatal (+)-[11C]DTBZ binding will be above normal in MA users during very early abstinence (4-7 days) and that levels might normalize in later abstinence (30 days). SIGNIFICANCE. Our study, designed and executed by investigators with extensive VMAT2 expertise in both the human and experimental animal, is a first step aimed at developing a brain biomarker that might identify those MA users who could receive benefit from dopamine substitution medication. In addition, the findings could provide unique information that could help interpretation of brain imaging VMAT2 data in neurology applications for which this biomarker has been proposed to assess efficacy of neuroprotective agents. PUBLIC HEALTH RELEVANCE: This study is aimed at obtaining brain imaging information that will ultimately help in the treatment of patients addicted to the drug methamphetamine. Results might also help in assessing the validity of a brain imaging tool that has been proposed for use in testing whether new neuroprotective drugs slow down the progression of Parkinson's disease.

描述（由申请方提供）：甲基苯丙胺使用者脑VMAT 2的PET成像研究目的。我们的广泛目标是获得人类甲基苯丙胺（MA）使用者的脑成像数据，这些数据可以帮助开发囊泡单胺转运蛋白（VMAT 2）作为生物标志物，以解释病理生理学并指导临床医生对吸毒者进行更适当的治疗干预。VMAT 2是负责人脑中单胺神经递质包装的突触囊泡转运蛋白，主要定位于人纹状体中的多巴胺能末梢，并且现在在本申请中被提出作为研究精神兴奋剂使用者中囊泡多巴胺状态的新工具。背景目前还没有有效的治疗兴奋剂MA成瘾的方法。尽管存在争议，但我们认为，正如我们的尸检结果所表明的那样，大脑神经递质多巴胺的缺乏可能是MA使用者的一些行为（特别是认知）问题的原因。然而，在体内数据表明多巴胺缺乏MA用户是缺乏的。在对MA使用者进行的一项试点正电子发射断层扫描（PET）研究中，我们意外地发现，在早期禁欲期间，纹状体（+）- [11 C]DTBZ与VMAT 2的结合增加，这一发现可以通过多巴胺之间的竞争减少来解释（在一些MA使用者中减少）和（+）-[11 C]DTBZ与VMAT 2的结合。由于囊泡多巴胺状态的体内生物标志物可能有助于为MA使用者选择最合适的治疗，因此需要在代表性数量的受试者中证实这些发现，并在纵向研究中确定结合水平是否在早期禁欲中下降。具体的目标、设计和假设。我们的主要具体目标是通过PET成像测量代表性数量的慢性MA使用者的纹状体（+）-[11 C]DTBZ结合，每个使用者在末次使用药物后4-7，12-15和28-30天进行评估，并在匹配的对照组中进行评估。根据我们的试验数据，我们的主要工作假设是，在早期戒断（4-7天）期间，MA使用者的纹状体（+）-[11 C]DTBZ结合将高于正常水平，并且在后期戒断（30天）水平可能恢复正常。意义我们的研究由在人类和实验动物中具有广泛VMAT 2专业知识的研究人员设计和执行，是旨在开发大脑生物标志物的第一步，该生物标志物可以识别那些可以从多巴胺替代药物中获益的MA用户。此外，这些发现可以提供独特的信息，有助于解释神经学应用中的脑成像VMAT 2数据，该生物标志物已被提议用于评估神经保护剂的疗效。 公共卫生相关性：这项研究的目的是获得大脑成像信息，最终将有助于对甲基苯丙胺成瘾患者的治疗。研究结果也可能有助于评估一种脑成像工具的有效性，该工具已被提议用于测试新的神经保护药物是否减缓帕金森病的进展。